Heterocyclic-Fused Pyrazolo[4,3-c] Pyridin-3-One M1 Receptor Positive Allosteric Modulators

ABSTRACT

The present invention is directed to heterocyclic fused pyrazole[4,3-c]pyridine-3-one compounds of formula (I): which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer&#39;s disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

FIELD OF THE INVENTION

The invention is directed to a class of heterocyclic-fusedpyrazolo[4,3-c]pyridin-3-one compounds, their salts, pharmaceuticalcompositions comprising them and their use in therapy of the human body.In particular, the invention is directed to a class of heterocyclicfused pyrazolo[4,3-c]pyridin-3-one compounds which are muscarinic M1receptor positive allosteric modulators, and hence are useful in thetreatment of Alzheimer's Disease and other diseases mediated by themuscarinic M1 receptor.

BACKGROUND OF THE INVENTION

Alzheimer's Disease is a common neurodegenerative disease affecting theelderly, resulting in progressive memory impairment, loss of languageand visuospatial skills, and behavior deficits. Characteristics of thedisease include degeneration of cholinergic neurons in the cerebralcortex, hippocampus, basal forebrain, and other regions of the brain,neurofibrillary tangles, and accumulation of the amyloid β peptide (Aβ).Aβ is a 39-43 amino acid produced in the brain by processing of thebeta-amyloid precursor protein (APP) by the beta-amyloid proteincleaving enzyme (“beta secretase” or “BACE”) and gamma-secretase. Theprocessing leads to accumulation of Aβ in the brain.

Cholinergic neurotransmission involves the binding of acetylcholineeither to the nicotinic acetylcholine receptor (nAChR) or to themuscarinic acetylcholine receptor (mAChR). It has been hypothesized thatcholinergic hypofunction contributes to the cognitive deficits ofpatients suffering from Alzheimer's Disease. Consequently, acetylcholinesterase inhibitors, which inhibit acetylcholine hydrolysis, havebeen approved in the United States for use in the treatment of thecognitive impairments of Alzheimer's Disease patients. While acetylcholinesterase inhibitors have provided some cognitive enhancement inAlzheimer's Disease patients, the therapy has not been shown to changethe underlying disease pathology.

A second potential pharmacotherapeutic target to counteract cholinergichypofunction is the activation of muscarinic receptors. Muscarinicreceptors are prevalent throughout the body. Five distinct muscarinicreceptors (M1-M5) have been identified in mammals. In the centralnervous system, muscarinic receptors are involved in cognitive,behavior, sensory, motor and autonomic functions. The muscarinic M1receptor, which is prevalent in the cerebral cortex, hippocampus andstriatum, has been found to have a major role in cognitive processingand is believed to have a role in the pathophysiology of Alzheimer'sDisease. See Eglen et al, TRENDS in Pharmacological Sciences, 2001,22:8, 409-414. In addition, unlike acetyl cholinesterase inhibitors,which are known to provide only symptomatic treatment, M1 agonists alsohave the potential to treat the underlying disease mechanism ofAlzheimer's Disease. The cholinergic hypothesis of Alzheimer's Diseaseis linked to both β-amyloid and hyperphosphorylated tau protein.Formation of β-amyloid may impair the coupling of the muscarinicreceptor with G-proteins. Stimulation of the M1 muscarinic receptor hasbeen shown to increase formation of the neuroprotective αAPPs fragment,thereby preventing the formation of the Aβ peptide. Thus, M1 agonistsmay alter APP processing and enhance αAPPs secretion. See Fisher, Jpn JPharmacol, 2000, 84:101-112 However, M1 ligands which have beendeveloped and studied for Alzheimer's Disease have produced side effectscommon to other muscarinic receptor ligands, such as sweating, nauseaand diarrhea. ee Spalding et al, Mol Pharmacol, 2002, 61:6, 1297-1302.

The muscarinic receptors are known to contain one or more allostericsites, which may alter the affinity with which muscarinic ligands bindto the primary binding or orthosteric sites. See, e.g., S. Lazareno etal, Mol Pharmacol, 2002, 62:6, 1491-1505; S. Lazareno et al, MolPharmacol, 2000, 58, 194-207.

Thus, the compounds of the invention, which are muscarinic M1 receptorpositive allosteric modulators, are believed to be useful in thetreatment of Alzheimer's Disease and other diseases mediated by themuscarinic M1 receptor.

SUMMARY OF THE INVENTION

The present invention is directed to heterocyclic-fusedpyrazolo[4,3-c]pyridin-3-one compounds of generic formula (I)

or a pharmaceutically acceptable salt thereof, which is useful as an M1receptor positive allosteric modulator.

The invention is further directed to methods of treating a patient(preferably a human) for diseases or disorders in which the M1 receptoris involved, such as Alzheimer's disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, by administering tothe patient a therapeutically effective amount of a compound of generalformula (I), or a pharmaceutically acceptable salt thereof. Theinvention is also directed to pharmaceutical compositions, which includean effective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier, andthe use of the compounds and pharmaceutical compositions of theinvention in the treatment of such diseases.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention is directed to heterocyclic-fusedpyrazolo[4,3-c]pyridin-3-one compounds of general formula (I)

and pharmaceutically acceptable salts thereof, whereinring A is saturated or unsaturated, and is formed from 3 or 4 ringatoms, selected from the group consisting of S, O, CH, CH₂, N and NH,wherein one or more of the ring atoms is optionally substituted by oneor more R¹;R¹ is optionally present at one or more of the ring A atoms, and each R¹is selected from the group consisting of

-   -   (1) halogen,    -   (2) —C₁₋₆ alkyl, or    -   (3) —OC₁₋₆ alkyl,    -   (4) hydroxyl,    -   wherein the alkyl R¹ moiety is optionally substituted with one        or more        -   (a) halogen,        -   (b) hydroxy,        -   (c) —O—C₁₋₆ alkyl,        -   (d) —C₂₋₈ alkenyl;            R² is optionally present at one or more of the ring carbon            atoms, and each R² is selected from the group consisting of    -   (1) halogen,    -   (2) —C₁₋₆ alkyl, or    -   (3) —OC₁₋₆ alkyl,    -   (4) hydroxyl,        R³ is selected from the group consisting of    -   (1) hydrogen,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₆₋₁₀ aryl,    -   (4) heteroaryl, which is an aromatic cyclic group, having from        five to twelve ring atoms, the ring atoms selected from C, O, N,        N→O or S, at least one of which is O, N, N→O or S,    -   wherein the alkyl, aryl or heteroaryl moiety is optionally        substituted with one or more        -   (a) halogen,        -   (b) hydroxyl,        -   (c) —C₁₋₆ alkyl,        -   (d) —O—C₁₋₆ alkyl,        -   (e) —C₃₋₈ cycloalkyl, or        -   (f) —C₆₋₁₀ aryl,            or R² and R³ together form a chain of 3 or 4 ring atoms,            selected from the group consisting of S, CH, CH₂, N and NH,            wherein one or more of the ring atoms is optionally            substituted by one or more    -   (a) halogen,    -   (b) —C₁₋₆ alkyl, or    -   (c) —OC₁₋₆ alkyl;        R⁴ is optionally present at one or more of the ring carbon        atoms, and each R⁴ is selected from the group consisting of    -   (1) halogen,    -   (2) —C₁₋₆ alkyl,    -   (3) —OC₁₋₆ alkyl, or    -   (4) hydroxyl; and

X is N or CH.

In particular embodiments of the compounds of formula (I), A forms oneof the following rings

In particular embodiments of the compounds of formula (I), R¹ is notpresent on ring A. In other embodiments, R¹ is present at one or two ofthe ring A atoms, and each R¹ is selected from the group consisting of

-   -   (1) halogen, or    -   (2) —C₁₋₆ alkyl,    -   wherein the alkyl R¹ moiety is optionally substituted with one        or more        -   (a) halogen, or        -   (b) —C₂₋₈ alkenyl.

In particular embodiments of the compounds of formula (I), R² is notpresent. In other embodiments, R² is present at one of the ring carbonatoms, and each R² is selected from the group consisting of

-   -   (1) halogen,    -   (2) —C₁₋₆ alkyl, or    -   (3) —OC₁₋₆ alkyl.

In particular embodiments of the compounds of formula (I), R³ isselected from the group consisting of

-   -   (1) —C₆₋₁₀ aryl (suitably, phenyl),    -   (2) heteroaryl, which is an aromatic cyclic group, having from        five to twelve ring atoms, the ring atoms selected from C, O, N,        N→O or S, at least one of which is O, N, N→O or S (suitably,        pyrazolyl),    -   wherein the alkyl, or heteroaryl moiety is optionally        substituted with one or more        -   (a) halogen,        -   (b) hydroxyl, or        -   (c) —C₁₋₆ alkyl.

One exemplary R³ heteroaryl group is heteroaryls having five ring atoms,the ring atoms selected from C, N, N→O and S, wherein one or two of thering atoms is N, N→O or S (for example, imidazolyl, pyrazolyl,thiazolyl).

Another exemplary R³ heteroaryl group is heteroaryls having six ringatoms, the ring atoms selected from C, N and N→O, wherein one or two ofthe ring atoms is N or N→O (for example, pyridyl, pyridyl N-oxide,pyrimidinyl).

Another exemplary R³ heteroaryl group is fused heteroaryls having nineor ten ring atoms, the ring atoms selected from C, O, N, N→O and S,wherein one, two or three of the ring atoms is O, N, N→O or S.

Suitably, R³ is pyrazolyl or phenyl.

In particular embodiments of the compounds of formula (I), R² and R³together form a chain of 3 or 4 ring atoms, selected from the groupconsisting of S, CH, CH₂, N and NH, wherein one or more of the ringatoms is optionally substituted by one or more

-   -   (a) halogen,    -   (b) —C₁₋₆ alkyl, or    -   (c) —OC₁₋₆ alkyl. For example, R² and R³ may together form the        chain —CH═N—NH—, which together with the phenyl group to which        R² and R³ are both linked forms the fused ring indazolyl, which        may be optionally substituted by one or more C₁₋₆ alkyl.

In particular embodiments of the compounds of formula (I), R⁴ is presentat one of the ring carbon atoms, and is selected from the groupconsisting of

-   -   (1) halogen (suitably, fluoro or chloro), or    -   (2) —C₁₋₆ alkyl (suitably methyl).

In particular embodiments of the compounds of formula (I), X is C. Inother embodiments, X is N.

In other embodiments of the compounds of formula (I), R⁴ is absent.

In certain embodiments, the compounds of formula (I) are compounds offormula (II)

and pharmaceutically acceptable salts thereof, wherein A, R¹, R² and R⁴are as described above.

In particular embodiments of the compounds of formula (II), A forms oneof the following rings

In particular embodiments of the compounds of formula (I), R¹ is notpresent on ring A. In other embodiments, R¹ is present at one or two ofthe ring A atoms, and each R¹ is selected from the group consisting of

-   -   (1) halogen, or    -   (2) —C₁₋₆ alkyl,    -   wherein the alkyl R¹ moiety is optionally substituted with one        or more        -   (a) halogen, or        -   (b) —C₂₋₈ alkenyl.

In particular embodiments of the compounds of formula (I), R² is notpresent. In other embodiments, R² is present at one of the ring carbonatoms, and each R² is selected from the group consisting of

-   -   (1) halogen,    -   (2) —C₁₋₆ alkyl, or    -   (3) —OC₁₋₆ alkyl.

In particular embodiments of the compounds of formula (I), R⁴ is presentat one of the ring carbon atoms, and is selected from the groupconsisting of

-   -   (1) halogen (suitably, fluoro or chloro), or    -   (2) —C₁₋₆ alkyl (suitably methyl).

In other embodiments of the compounds of formula (I), R⁴ is absent.

Specific embodiments of formula (I) are described herein as Examples1-16, as set forth below:

-   2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,5-naphthyridin-3-one;-   2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,8-naphthyridin-3-one;-   2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,8-naphthyridin-3-one;-   2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,7-naphthyridin-3-one;-   2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,6-naphthyridin-3-one;-   2-(2-Methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[3′,4′:4,5]-pyrido[2,3-b]pyrazin-3-one;-   5-(Biphenyl-4-ylmethyl)-2-(2-fluorophenyl)-5,6,7,8-tetrahydrocyclopenta[b]pyrazolo[3,4-d]pyridine-3(2H)-one;-   2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-5,6,7,8-tetrahydrocyclopenta[b]pyrazolo[3,4-d]pyridine-3(2H)-one;-   2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-d]pyridine-3(2H)-one;-   (±)-2-(2-Fluorophenyl)-9-(prop-2-en-1-yloxy)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[4,3-c]quinolin-3-one;-   (±)-2-(2-Fluorophenyl)-9-hydroxy-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[4,3-c]quinolin-3-one;-   2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,-dihydro-3H-pyrazolo[4,3-d]thieno[3,2-b]pyridin-3-one;-   2-(2-Methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,-dihydro-3H-pyrazolo[3,4-d]thieno[3,2-b]pyridin-3-one;-   2-(2-Fluorophenyl)-5-[(1-methyl-1H-indazol-5-yl)methyl]-2,5,-dihydro-3H-pyrazolo[4,3-d]thieno[3,2-b]pyridin-3-one;-   2-(3,5-Dichloropyridin-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,-dihydro-3H    pyrazolo[3,4-c]thieno[3,2-b]pyridin-3-one;-   5-{[4-(1H-Pyrazol-1-yl)phenyl]methyl}-2-pyridin-4-yl-2,5,-dihydro-3H-pyrazolo[3,4-d]thieno[3,2-b]pyridin-3-one;    and pharmaceutically acceptable salts thereof.

The invention is also directed to methods of treating a patient(preferably a human) for diseases or disorders in which the M1 receptoris involved, such as Alzheimer's Disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, by administering tothe patient a therapeutically effective amount of a compound of formulas(I) or (II), or a pharmaceutically acceptable salt thereof.

The invention is also directed to the use of a compound of formulas (I)or (II), for treating a disease or disorder in which the M1 receptor isinvolved, such as Alzheimer's Disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, by administering tothe patient a compound of formulas (I) or (II), or a pharmaceuticallyacceptable salt thereof.

The invention is also directed to medicaments or pharmaceuticalcompositions for the treatment of diseases or disorders in a patient(preferably a human) in which the M1 receptor is involved, such asAlzheimer's Disease, cognitive impairment, schizophrenia, paindisorders, and sleep disorders, which comprise a compound of formulas(I) or (II), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

The invention is also directed to a method for the manufacture of amedicament or a pharmaceutical composition for treating diseases inwhich M1 receptor is involved, such as Alzheimer's Disease, cognitiveimpairment, schizophrenia, pain disorders, and sleep disorders,comprising combining a compound of formulas (I) or (II), or apharmaceutically acceptable salt thereof, with a pharmaceuticallyacceptable carrier.

Where a variable occurs more than once in any of formulas (I) or (II),or in a substituent thereof, the individual occurrences of that variableare independent of each other, unless otherwise specified.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent, means a saturated straight or branched chain hydrocarbonradical having the number of carbon atoms designated (e.g., C₁₋₁₀ alkylmeans an alkyl group having from one to ten carbon atoms). Preferredalkyl groups for use in the invention are C₁₋₆ alkyl groups, having fromone to six atoms. Exemplary alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, andthe like. C₀ alkyl means a bond.

As used herein, the term “alkenyl,” by itself or as part of anothersubstituent, means a straight or branched chain hydrocarbon radicalhaving a single carbon-carbon double bond and the number of carbon atomsdesignated (e.g., C₂₋₁₀ alkenyl means an alkenyl group having from twoto ten carbon atoms). Preferred alkenyl groups for use in the inventionare C₂₋₆ alkenyl groups, having from two to six carbon atoms. Exemplaryalkenyl groups include ethenyl and propenyl.

As used herein, the term “aryl,” by itself or as part of anothersubstituent, means an aromatic cyclic hydrocarbon radical. Preferredaryl groups have from six to ten carbons atoms. The term “aryl” includesmultiple ring systems as well as single ring systems. Preferred arylgroups for use in the invention include phenyl and naphthyl.

The term “aryl” also includes fused cyclic hydrocarbon rings which arepartially aromatic (i.e., one of the fused rings is aromatic and theother is non-aromatic). An exemplary aryl group which is partiallyaromatic is indanyl.

As used herein, the term “heteroaryl,” by itself or as part of anothersubstituent, means a cyclic or polycyclic group having from five totwelve ring atoms selected from C, N, N→O, O and S, wherein at least onering heteroatom is O, N, N→O or S, and wherein at least one of theconstituent rings is aromatic. Exemplary heteroaryl groups for use inthe invention include carbazolyl, carbolinlyl, chromenyl, cinnolinyl,furanyl, benzofuranyl, benzofurazanyl, isobenzofuranyl, imidazolyl,benzimidazolyl, benzimidazolonyl, indazolyl, indolyl, isoindolyl,indolinyl, indolazinyl, indynyl, oxadiazolyl, oxazolyl, benzoxazolyl,isoxazolyl, pyranyl, pyrazinyl, pyrazolyl, benzopyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolyl, quinolyl, isoquinolyl, tetrazolyl,thiazolyl, isothiazolyl, thiadiazolyl, thienyl, benzothioenyl,benzothiazolyl, quinoxalinyl, triazinyl and triazolyl, and N-oxidesthereof.

One subgroup of heteroaryl groups have five ring atoms, the ring atomsselected from C, N, N→O or S, wherein one or two of the ring atoms is N,N→O or S. Exemplary heteroaryl groups in this embodiment are imidazolyl,pyrazolyl and thiazolyl.

Another subgroup of heteroaryl groups have six ring atoms, the ringatoms selected from C, N and N→O, wherein one or two of the ring atomsis N or N→O. Exemplary heteroaryl groups in this embodiment are pyridyl,pyridyl N-oxide and pyrimidinyl.

Another subgroup of heteroaryl groups have nine or ten ring atoms, thering atoms selected from C, N, N→O and S, wherein one or two of the ringatoms is N, N→O or S.

The term “heteroaryl” also includes fused cyclic heterocyclic ringswhich are partially aromatic (i.e., one of the fused rings is aromaticand the other is non-aromatic). An exemplary heteroaryl group which ispartially aromatic is benzodioxol.

When a heteroaryl group as defined herein is substituted, thesubstituent may be bonded to a ring carbon atom of the heteroaryl group,or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which hasa valence which permits substitution. Preferably, the substituent isbonded to a ring carbon atom. Similarly, when a heteroaryl group isdefined as a substituent herein, the point of attachment may be at aring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e.,a nitrogen, oxygen or sulfur), which has a valence which permitsattachment. Preferably, the attachment is at a ring carbon atom.

As used herein, the term “halo” or “halogen” includes fluoro, chloro,bromo and iodo.

The compounds of the invention may have one or more asymmetric centers.Compounds with asymmetric centers give rise to enantiomers (opticalisomers), diastereomers (configurational isomers) or both, and it isintended that all of the possible enantiomers and diastereomers inmixtures and as pure or partially purified compounds are included withinthe scope of this invention. The present invention is meant to encompassall such isomeric forms of the compounds of formulas (I) or (II).

Formulas (I) or (II) are shown above without a definite stereochemistry.The present invention includes all stereoisomers of formulas (I) or(II), and pharmaceutically acceptable salts thereof.

The independent syntheses of the enantiomerically or diastereomericallyenriched compounds, or their chromatographic separations, may beachieved as known in the art by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by the x-ray crystallography of crystalline products orcrystalline intermediates that are derivatized, if necessary, with areagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers or diastereomers are isolated. The separationcan be carried out by methods well known in the art, such as thecoupling of a racemic mixture of compounds to an enantiomerically purecompound to form a diastereomeric mixture, followed by separation of theindividual diastereomers by standard methods, such as fractionalcrystallization or chromatography. The coupling reaction is often theformation of salts using an enantiomerically pure acid or base. Thediastereomeric derivatives may then be converted to the pure enantiomersby cleavage of the added chiral residue. The racemic mixture of thecompounds can also be separated directly by chromatographic methodsusing chiral stationary phases, which methods are well known in the art.

Alternatively, any enantiomer or diastereomer of a compound may beobtained by stereoselective synthesis using optically pure startingmaterials or reagents of known configuration by methods well known inthe art.

In the compounds of formulas (I) or (II), the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofgeneric formulas (I) or (II). For example, different isotopic forms ofhydrogen (H) include protium (¹H) and deuterium (²H). Protium is thepredominant hydrogen isotope found in nature. Enriching for deuteriummay afford certain therapeutic advantages, such as increasing in vivohalf-life or reducing dosage requirements, or may provide a compounduseful as a standard for characterization of biological samples.Isotopically-enriched compounds within generic formulas (I) or (II) canbe prepared without undue experimentation by conventional techniqueswell known to those skilled in the art or by processes analogous tothose described in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

The term “substantially pure” means that the isolated material is atleast 90% pure, and preferably 95% pure, and even more preferably 99%pure as assayed by analytical techniques known in the art.

As used herein, the term “muscarinic M1 receptor” refers to one of thefive subtypes of the muscarinic acetylcholine receptor, which is fromthe superfamily of G-protein coupled receptors. The family of muscarinicreceptors is described, for example, in Pharmacol Ther, 1993,58:319-379; Eur J Pharmacol, 1996, 295:93-102, and Mol Pharmacol, 2002,61:1297-1302. The muscarinic receptors are known to contain one or moreallosteric sites, which may alter the affinity with which muscarinicligands bind to the primary binding or orthosteric sites. See, e.g., S.Lazareno et al, Mol Pharmacol, 2002, 62:6, 1491-1505.

As used herein, the terms “positive allosteric modulator” and“allosteric potentiator” are used interchangeably, and refer to a ligandwhich interacts with an allosteric site of a receptor to activate theprimary binding site. The compounds of the invention are positiveallosteric modulators of the muscarinic M1 receptor. For example, amodulator or potentiator may directly or indirectly augment the responseproduced by the endogenous ligand (such as acetylcholine or xanomeline)at the orthosteric site of the muscarinic M1 receptor in an animal, inparticular, a human.

The actions of ligands at allosteric receptor sites may also beunderstood according to the “allosteric ternary complex model,” as knownby those skilled in the art. The allosteric ternary complex model isdescribed with respect to the family of muscarinic receptors in Birdsallet al, Life Sciences, 2001, 68:2517-2524. For a general description ofthe role of allosteric binding sites, see Christopoulos, Nature Reviews:Drug Discovery, 2002, 1:198-210.

It is believed that the compounds of the invention bind to an allostericbinding site that is distinct from the orthosteric acetylcholine site ofthe muscarinic M1 receptor, thereby augmenting the response produced bythe endogenous ligand acetylcholine at the orthosteric site of the M1receptor. It is also believed that the compounds of the invention bindto an allosteric site which is distinct from the xanomeline site of themuscarinic M1 receptor, thereby augmenting the response produced by theendogenous ligand xanomeline at the orthosteric site of the M1 receptor.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. The compoundsof the invention may be mono, di or tris salts, depending on the numberof acid functionalities present in the free base form of the compound.Free bases and salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like.

Salts in the solid form may exist in more than one crystal structure,and may also be in the faun of hydrates. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, trifluoroacetic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric,para-toluenesulfonic acid, and the like.

The present invention is directed to the use of the compounds offormulae (I) to (III) disclosed herein as M1 allosteric modulators in apatient or subject such as a mammal in need of such activity, comprisingthe administration of an effective amount of the compound. In additionto humans, a variety of other mammals can be treated according to themethod of the present invention.

The compounds of the present invention have utility in treating orameliorating Alzheimer's disease. The compounds may also be useful intreating or ameliorating other diseases mediated by the muscarinic M1receptor, such as schizophrenia, sleep disorders, pain disorders(including acute pain, inflammatory pain and neuropathic pain) andcognitive disorders (including mild cognitive impairment). Otherconditions that may be treated by the compounds of the invention includeParkinson's Disease, pulmonary hypertension, chronic obstructivepulmonary disease (COPD), asthma, urinary incontinence, glaucoma,schizophrenia, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy,degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosisof the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders,amyotrophic lateral sclerosis, progressive supranuclear palsy, headtrauma, stroke, pancreatitis, inclusion body myositis, other peripheralamyloidoses, diabetes, autism and atherosclerosis.

In preferred embodiments, the compounds of the invention are useful intreating Alzheimer's Disease, cognitive disorders, schizophrenia, paindisorders and sleep disorders.

For example, the compounds may be useful for the prevention of dementiaof the Alzheimer's type, as well as for the treatment of early stage,intermediate stage or late stage dementia of the Alzheimer's type. Ingeneral, Alzheimer's Disease symptoms include confusion, irritabilityand aggression, mood swings, language breakdown, long-term memory loss,and the general withdrawal of the sufferer as their senses decline. Thelanguage problems associated with Alzheimer's Disease include ashrinking vocabulary and decreased word fluency. Alzheimer's Diseasealso includes impairment of fine motor tasks, such as writing, drawing,dressing and other coordinated movements. Alzheimer's Disease symptomsinclude apraxia (difficulties in movement planning).

Early stage Alzheimer's Disease is characterized by confusion, memoryloss and changes in other cognitive abilities. Symptoms may includegetting lost, trouble handling money and paying bills, repeatingquestions, taking longer to complete normal daily tasks, poor judgment,and mood and personality changes.

Intermediate stage Alzheimer's Disease is manifested by problems withreasoning, sensory processing, and conscious thought. Intermediate stagesymptoms include continuing memory loss and confusion. Intermediatestage patients typically begin to have problems recognizing family andfriends. Symptoms include the inability to learn new things, carry outtasks that involve multiple steps (such as getting dressed), or copingwith new situations. Intermediate stage patients may havehallucinations, delusions, and paranoia, and may behave impulsively.

Patients suffering from severe Alzheimer's Disease are typically unableto communicate and are completely dependent on others for their care.

Potential schizophrenia conditions or disorders for which the compoundsof the invention may be useful include one or more of the followingconditions or diseases: schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniforin disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (phencyclidine, ketanine and other dissociativeanaesthetics, amphetamine and other psychostimulants and cocaine)psychosispsychotic disorder, psychosis associated with affectivedisorders, brief reactive psychosis, schizoaffective psychosis,“schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, or illness associated with psychosis (such asmajor depression, manic depressive (bipolar) disorder, Alzheimer'sdisease and post-traumatic stress syndrome), including both the positiveand the negative symptoms of schizophrenia and other psychoses;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, multi-infarct dementia, trauma, vascular problems orstroke, HIV disease, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeldt-Jacob disease, perinatal hypoxia, other generalmedical conditions or substance abuse); delirium, amnestic disorders orage related cognitive decline.

In another specific embodiment, the present invention provides a methodfor treating schizophrenia or psychosis comprising administering to apatient in need thereof an effective amount of a compound of the presentinvention. Particular schizophrenia or psychosis pathologies areparanoid, disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. At present, the text revision ofthe fourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. As used herein, the term“schizophrenia or psychosis” includes treatment of those mentaldisorders as described in DSM-IV-TR. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies and classificationsystems for mental disorders, and that these systems evolve with medicaland scientific progress. Thus the term “schizophrenia or psychosis” isintended to include like disorders that are described in otherdiagnostic sources.

Examples of combinations of the compounds include combinations withagents for the treatment of schizophrenia, for example in combinationwith sedatives, hypnotics, anxiolytics, antipsychotics, antianxietyagents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minortranquilizers, melatonin agonists and antagonists, melatonergic agents,benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as:adinazolam, allobarbital, alonimid, aiprazolam, amisulpride,amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide,clorethate, chlorpromazine, clozapine, cyprazepam, desipramine,dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine,doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam,flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine,fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine,imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone,melatonin, mephobarbital, meprobamate, methaqualone, midaflur,midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone,roletamide, secobarbital, sertraline, suproelone, temazepam,thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone,triazolam, trepipam, tricetamide, triclofos, trifluoperazine,trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon,ziprasidone, zolazepam, zolpidem, and salts thereof, and combinationsthereof, and the like, or the subject compound may be administered inconjunction with the use of physical methods such as with light therapyor electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol)hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, Ataadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with the subject compoundmay be in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form. Thus, the subject compound may beemployed in combination with acetophenazine, alentemol, aripiprazole,amisuipride, benzhexol, bromocriptine, biperiden, chlorpromazine,chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine,haloperidol, levodopa, levodopa with benserazide, levodopa withcarbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide,olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine,risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine,thiothixene, trifluoperazine or ziprasidone.

Potential sleep conditions or disorders for which the compounds of theinvention may be useful include enhancing sleep quality; improving sleepquality; augmenting sleep maintenance; increasing the value which iscalculated from the time that a subject sleeps divided by the time thata subject is attempting to sleep; decreasing sleep latency or onset (thetime it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; increasing daytime alertness;reducing daytime drowsiness; treating or reducing excessive daytimesleepiness; insomnia; hypersomnia; narcolepsy; interrupted sleep; sleepapnea; wakefulness; nocturnal myoclonus; REM sleep interruptions;jet-lag; shift workers' sleep disturbances; dyssomnias; night terror;insomnias associated with depression, emotional/mood disorders, as wellas sleep walking and enuresis, and sleep disorders which accompanyaging; Alzheimer's sundowning; conditions associated with circadianrhythmicity as well as mental and physical disorders associated withtravel across time zones and with rotating shift-work schedules;conditions due to drugs which cause reductions in REM sleep as a sideeffect; syndromes which are manifested by non-restorative sleep andmuscle pain or sleep apnea which is associated with respiratorydisturbances during sleep; and conditions which result from a diminishedquality of sleep.

Pain disorders for which the compounds of the invention may be usefulinclude neuropathic pain (such as postherpetic neuralgia, nerve injury,the “dynias”, e.g., vulvodynia, phantom limb pain, root avulsions,painful diabetic neuropathy, painful traumatic mononeuropathy, painfulpolyneuropathy); central pain syndromes (potentially caused by virtuallyany lesion at any level of the nervous system); postsurgical painsyndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stumppain); bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia); perioperative pain (general surgery, gynecological),chronic pain, dysmennorhea, as well as pain associated with angina, andinflammatory pain of varied origins (e.g. osteoarthritis, rheumatoidarthritis, rheumatic disease, teno-synovitis and gout), headache,migraine and cluster headache, headache, primary hyperalgesia, secondaryhyperalgesia, primary allodynia, secondary allodynia, or other paincaused by central sensitization.

Compounds of the invention may also be used to treat or preventdyskinesias. Furthermore, compounds of the invention may be used todecrease tolerance and/or dependence to opioid treatment of pain, andfor treatment of withdrawal syndrome of e.g., alcohol, opioids, andcocaine.

The subject or patient to whom the compounds of the present invention isadministered is generally a human being, male or female, in whom M1allosteric modulation is desired, but may also encompass other mammals,such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys,chimpanzees or other apes or primates, for which treatment of the abovenoted disorders is desired.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment of diseases or conditions forwhich the compounds of the present invention have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Additionally, the compounds of the present inventionmay be used in combination with one or more other drugs that treat,prevent, control, ameliorate, or reduce the risk of side effects ortoxicity of the compounds of the present invention. Such other drugs maybe administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with the compounds of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to the compounds of the present invention. Thecombinations may be administered as part of a unit dosage formcombination product, or as a kit or treatment protocol wherein one ormore additional drugs are administered in separate dosage forms as partof a treatment regimen.

Examples of combinations of the compounds of the present inventioninclude combinations with anti-Alzheimer's Disease agents, for examplebeta-secretase inhibitors; alpha 7 nicotinic agonists; ADAM 10 ligandsor activators; gamma-secretase inhibitors; gamma secretase modulators;tau phosphorylation inhibitors; glycine transport inhibitors; LXR βagonists; ApoE4 conformational modulators; NR2B antagonists; androgenreceptor modulators; blockers of Aβ oligomer formation; 5-HT4 agonists;5-HT6 antagonists; 5-HT1a antagonists, such as lecozotan; p25/CDK5inhibitors; NK1/NK3 receptor antagonists; COX-2 inhibitors; HMG-CoAreductase inhibitors; NSAIDs including ibuprofen; vitamin E;anti-amyloid antibodies (including anti-amyloid humanized monoclonalantibodies), such as bapineuzumab; anti-inflammatory compounds such as(R)-flurbiprofen, nitroflurbiprofen; PPAR gamma agonists, such aspioglitazone and rosiglitazone; CB-1 receptor antagonists or CB-1receptor inverse agonists; antibiotics such as doxycycline and rifampin;N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine andneramexane; cholinesterase inhibitors such as galantamine,rivastigrnine, donepezil, tacrine, phenserine and ladostigil; growthhormone secretagogues such as ibutamoren, ibutamoren mesylate, andcapromorelin; histamine H₃ receptor antagonists; AMPA agonists or AMPAmodulators; PDE IV inhibitors; PDE10A inhibitors; GABA_(A) inverseagonists; GSK3β inhibitors; neuronal nicotinic agonists; selective M1agonists; HDAC inhibitors; and microtubule affinity regulating kinase(MARK) ligands; or other drugs that affect receptors or enzymes thateither increase the efficacy, safety, convenience, or reduce unwantedside effects or toxicity of the compounds of the present invention.

Examples of combinations of the compounds include combinations withagents for the treatment of pain, for example non-steroidalanti-inflammatory agents, such as aspirin, diclofenac, duflunisal,fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen,ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2inhibitors, such as celecoxib, rofecoxib and valdecoxib; CB-2 agonists;VR-1 antagonists; bradykinin B1 receptor antagonists; sodium channelblockers and antagonists; nitric oxide synthase (NOS) inhibitors(including iNOS and nNOS inhibitors); glycine site antagonists,including lacosamide; neuronal nicotinic agonists; NMDA antagonists;potassium channel openers; AMPA/kainate receptor antagonists; calciumchannel blockers, such as ziconotide; GABA-A receptor IO modulators(e.g., a GABA-A receptor agonist); matrix metalloprotease (MMP)inhibitors; thrombolytic agents; opioid analgesics such as codeine,fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine,oxycodone, oxymorphone, pentazocine, propoxyphene; neutrophil inhibitoryfactor (NIF); pramipexole, ropinirole; anticholinergics; amantadine;monoamine oxidase B15 (“MAO-B”) inhibitors; 5HT receptor agonists orantagonists; mGlu5 antagonists; alpha agonists; neuronal nicotinicagonists; NMDA receptor agonists or antagonists; NK1 antagonists;selective serotonin reuptake inhibitors (“SSRI”) and/or selectiveserotonin and norepinephrine reuptake inhibitors (“SSNRI”), such asduloxetine; tricyclic antidepressant drugs, norepinephrine modulators;lithium; valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan;naratriptan and sumatriptan.

The compounds of the present invention may be administered incombination with compounds useful for enhancing sleep quality andpreventing and treating sleep disorders and sleep disturbances,including e.g., sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, antihistamines, benzodiazepines, barbiturates,cyclopyrrolones, orexin antagonists, alpha-1 antagonists, GABA agonists,5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2Cantagonists, histamine antagonists including histamine H3 antagonists,histamine H3 inverse agonists, imidazopyridines, minor tranquilizers,melatonin agonists and antagonists, melatonergic agents, other orexinantagonists, orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nottaptyline, oxazepam, paraldehyde,paroxetine, pentobarbital, perlapine, perphenazine, phenelzine,phenobarbital, prazepam, promethazine, propofol, protriptyline,quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline,suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and saltsthereof, and combinations thereof, and the like, or the compound of thepresent invention may be administered in conjunction with the use ofphysical methods such as with light therapy or electrical stimulation.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. This term in relation to pharmaceutical compositionsis intended to encompass a product comprising one or more activeingredients, and an optional carrier comprising inert ingredients, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients.

In general, pharmaceutical compositions are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation. In thepharmaceutical composition the active compound, which is a compound offormulae (I) to (VIII), is included in an amount sufficient to producethe desired effect upon the process or condition of diseases.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tablets maycontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient.

Compositions for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Other pharmaceutical compositions include aqueous suspensions, whichcontain the active materials in admixture with excipients suitable forthe manufacture of aqueous suspensions. In addition, oily suspensionsmay be formulated by suspending the active ingredient in a vegetableoil, for example arachis oil, olive oil, sesame oil or coconut oil, orin a mineral oil such as liquid paraffin. Oily suspensions may alsocontain various excipients. The pharmaceutical compositions of theinvention may also be in the form of oil-in-water emulsions, which mayalso contain excipients such as sweetening and flavoring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension, or in the form of sterilepowders for the extemporaneous preparation of such sterile injectablesolutions or dispersions. In all cases, the final injectable form mustbe sterile and must be effectively fluid for easy syringability. Thepharmaceutical compositions must be stable under the conditions ofmanufacture and storage; thus, preferably should be preserved againstthe contaminating action of microorganisms such as bacteria and fungi.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared via conventional processing methods. As anexample, a cream or ointment is prepared by mixing hydrophilic materialand water, together with about 5 wt % to about 10 wt % of the compound,to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can also be in a formsuitable for rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” or “administering a” compound should beunderstood to mean providing a compound of the invention to theindividual in need of treatment in a form that can be introduced intothat individual's body in a therapeutically useful form andtherapeutically useful amount, including, but not limited to: oraldosage forms, such as tablets, capsules, syrups, suspensions, and thelike; injectable dosage forms, such as IV, IM, or IP, and the like;transdermal dosage forms, including creams, jellies, powders, orpatches; buccal dosage forms; inhalation powders, sprays, suspensions,and the like; and rectal suppositories.

The terms “effective amount” or “therapeutically effective amount” meansthe amount of the subject compound that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treatment” or “treating” means anyadministration of a compound of the present invention and includes (1)inhibiting the disease in an animal that is experiencing or displayingthe pathology or symptomatology of the diseased (i.e., arresting furtherdevelopment of the pathology and/or symptomatology), or (2) amelioratingthe disease in an animal that is experiencing or displaying thepathology or symptomatology of the diseased (i.e., reversing thepathology and/or symptomatology).

The compositions containing compounds of the present invention mayconveniently be presented in unit dosage faun and may be prepared by anyof the methods well known in the art of pharmacy. The term “unit dosageform” is taken to mean a single dose wherein all active and inactiveingredients are combined in a suitable system, such that the patient orperson administering the drug to the patient can open a single containeror package with the entire dose contained therein, and does not have tomix any components together from two or more containers or packages.Typical examples of unit dosage forms are tablets or capsules for oraladministration, single dose vials for injection, or suppositories forrectal administration. This list of unit dosage forms is not intended tobe limiting in any way, but merely to represent typical examples of unitdosage forms.

The compositions containing compounds of the present invention mayconveniently be presented as a kit, whereby two or more components,which may be active or inactive ingredients, carriers, diluents, and thelike, are provided with instructions for preparation of the actualdosage form by the patient or person administering the drug to thepatient. Such kits may be provided with all necessary materials andingredients contained therein, or they may contain instructions forusing or making materials or components that must be obtainedindependently by the patient or person administering the drug to thepatient.

When treating or ameliorating a disorder or disease for which compoundsof the present invention are indicated, generally satisfactory resultsare obtained when the compounds of the present invention areadministered at a daily dosage of from about 0.1 mg to about 100 mg perkg of animal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Thetotal daily dosage is from about 1.0 mg to about 2000 mg, preferablyfrom about 0.1 mg to about 20 mg per kg of body weight. In the case of a70 kg adult human, the total daily dose will generally be from about 7mg to about 1,400 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response. The compounds may be administered on aregimen of 1 to 4 times per day, preferably once or twice per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.005 mg to about 2.5 g of active agent,compounded with an appropriate and convenient amount of carriermaterial. Unit dosage forms will generally contain between from about0.005 mg to about 1000 mg of the active ingredient, typically 0.005,0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twiceor three times a day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The compounds of the invention may be prepared according to thefollowing reaction Schemes, in which variables are as defined before orare derived, using readily available starting materials, from reagentsand conventional synthetic procedures. It is also possible to usevariants, which are themselves known to those of ordinary skill inorganic synthesis art, but are not mentioned in greater detail.

The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds of theinvention.

Compound 1 is a heterocyclic amine that can undergo a substitutionreaction with diethyl ethoxymethylenemaloate (2) at elevated temperatureto afford the vinylogous amide 3. Cyclization can be achieved atelevated temperature in diphenyl ether to afford 4. N-Alkylation with anappropriately substituted benzylic halide in the presence of a base,such as potassium carbonate, and in the presence of a catalyst, such aspotassium iodide, can afford the alkylated compound 6, which can beconverted to the thioketone 7 in the presence of Lawesson's Reagent atelevated temperature. Treatment of thioketone 7 with a suitablysubstituted hydrazine 8 in the presence of a base, such as potassiumcarbonate, at elevated temperature can provide 12. Alternatively,treatment of 7 with hydrazine, in the presence of a base such aspotassium carbonate, can afford the unsubstituted pyrazolone 9. Upontreatment of 9 with a suitably substituted aryl halide 10, in thepresence of copper(I) iodide, a base such as potassium phosphate, aligand, such as (±)-trans-N,N-dimethylcyclohexane-1,2-diamine, in asolvent such as N,N-dimethylformamide at elevated temperature can alsoprovide compounds like 12. Treatment of ketone 6 with phosphorusoxychloride can afford the chloroquinolinium salt 11, which upontreatment with a suitably substituted hydrazine 8, in the presence of abase such as potassium carbonate, can provide compounds like 12.

During any of the above synthetic sequences it may be necessary ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973, and T. W.Greene & P/G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1999. The protecting groups may be removed at a convenientsequent stage using methods known from the art.

Several methods for preparing the compounds of this invention areillustrated in the schemes and examples herein. Starting materials aremade according to procedures known in the art or as illustrated herein.The following examples are provided so that the invention might be morefully understood.

Example 12-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,5-naphthyridin-3-one

Step 1: Preparation ofdiethyl[pyridin-3-ylamino)methylidene]propanedioate: 3-Aminopyridine(1.1 g, 11 mmol) and diethyl ethoxymethylenemaloate (2.3 mL, 11 mmol, 1equiv) were combined and placed into a preheated oil bath at 80° C. for14 hours. The mixture was cooled to ambient temperature, upon which asolid was formed. The mixture was filtered, the filtrate was discardedand the solid was washed with hexanes and dried in vacuo to provide thetitled compound.

Step 2: Preparation of ethyl4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate: To a solution ofdiphenyl ether (30 mL) at 250° C. was added a 1 mL diphenylethersolution of diethyl [(pyridin-3-ylamino)methylidene]propanedioate (0.80g, 3.0 mmol) dropwise over 5 minutes. After 30 minutes, the mixture wascooled to ambient temperature, diluted with hexanes (100 mL) andfiltered. The solid was dried in vacuo, providing the titled compound.

Step 3: Preparation of ethyl4-oxo-1-{[4-(1H-pyrazolo-1-yl)phenyl]methyl}-1,4-dihydro-1,5-naphthyridine-3-carboxylate:Ethyl 4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (0.10 g, 0.46mmol), 1-[4-(bromomethyl)phenyl]-1H-pyrazole (0.12 g, 0.50 mmol, 1.1equiv), potassium carbonate (0.19 g, 1.4 mmol, 3 equiv) and potassiumiodide (7.6 mg, 0.046 mmol, 0.1 equiv) were combined inN,N-dimethylformamide (3 mL) and stirred for 3 hours. The mixture waspoured into sodium bicarbonate (200 mL, aqueous saturated) and extractedwith chloroform containing 10% methanol (3×100 mL). The combined organicextracts were dried with sodium sulfate, filtered and concentrated invacuo. The residue was purified by silica gel gradient chromatography(100:0 to 80:20; chloroform:methanol containing 10% ammonium hydroxide),providing the titled compound.

Step 4: Preparation of ethyl1-{[4-(1H-pyrazolo-t-yl)phenyl]methyl}-4-thioxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate:Ethyl4-oxo-1-{[4-(1H-pyrazolo-1-yl)phenyl]methyl}-1,4-dihydro-1,5-naphthyridine-3-carboxylate(25 mg, 0.067 mmol) was dissolved in chloroform (3 mL), diluted withtoluene (3 mL) and treated with2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide(Lawesson's Reagent, 27 mg, 0.067 mmol, 1 equiv). The mixture was heatedto 80° C. and after 30 minutes, 1,2-dimethoxyethane (3 mL) was added andthe mixture was heated to 90° C. After 30 minutes, additional Lawesson'sReagent (27 mg, 0.067 mmol, 1 equiv) was added and the mixture washeated at 90° C. for an additional 1 hour. The mixture was cooled toambient temperature, concentrated in vacuo and purified by silica gelgradient chromatography (100:0 to 0:100; hexanes:ethyl acetatecontaining 5% methanol), providing the titled compound.

Step 5: Preparation of5-{[4-(1H-pyrazolo-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,5-naphthyridin-3-one:Ethyl1-{[4-(1H-pyrazolo-1-yl)phenyl]methyl}-4-thioxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate(10 mg, 0.026 mmol) was suspended in 1,2-dimethoxyethane (2 mL) andtreated with hydrazine (1.2 mg, 0.038 mmol, 1.5 equiv) and potassiumcarbonate (28 mg, 0.20 mmol, 8 equiv). The mixture was placed into apreheated oil bath at 80° C. for 1 hour, cooled to ambient temperatureand filtered. The filtrate was concentrated in vauco to provide thetitled compound.

Step 6: Preparation of2-(2-fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,5-naphthyridin-3-one:5-{[4-(1H-Pyrazolo-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,5-naphthyridin-3-one(8 mg, 0.023 mmol), 2-fluoroiodobenzene (10 mg, 0.047 mmol, 2 equiv),(±)-trans-N,N-dimethylcyclohexane-1,2-diamine (3.3 mg, 0.023 mmol, 1equiv), copper (I) iodide (1.8 mg, 9.3 μmol, 0.4 equiv) and potassiumphosphate (20 mg, 0.12 mmol, 5 equiv) were combined in degassedN,N-dimethylformamide (1 mL) and placed into a preheated oil bath at115° C. for 16 hours. The mixture was cooled to ambient temperature,poured into sodium bicarbonate (15 mL, aqueous saturated) and extractedwith dichloromethane (2×15 mL). The combined organic extracts were driedwith sodium sulfate, filtered and concentrated in vacuo. The residue waspurified by silica gel gradient chromatography (100:0 to 90:10dichloromethane:methanol), providing the titled compound: ¹H-NMR (400MHz, CDCl₃) δ 8.80 (1H, d, J=4.2 Hz), 8.45 (1H, s), 7.92 (1H, d, J=2.6Hz), 7.76-7.68 (5H, m), 7.44 (1H, dd, J=8.7, 4.4 Hz), 7.38-7.33 (1H, m),7.30 (2H, d, J=8.6 Hz), 7.27-7.21 (2H, m), 6.49 (1H, dd, J=2.5, 1.9 Hz),5.48 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 437.1514[(M+H)⁺; calculated for C₂₅H₁₈FN₆O: 437.1521].

Example 22-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,8-naphthyridin-3-one

Using the procedures described in Example 1, substituting ethyl4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate for ethyl4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Step 3), the titledcompound was obtained: ¹H-NMR (400 MHz, d⁶-DMSO) δ 9.28 (1H, s), 8.77(1H, dd, J=4.7, 1.8 Hz), 8.59 (1H, dd, J=8.0, 1.9 Hz), 8.44 (1H, d,J=2.5 Hz), 7.79 (2H, d, J=8.7 Hz), 7.72 (1H, d, J=1.6 Hz), 7.63-7.56(2H, m), 7.55 (2H, d, J=8.5 Hz), 7.49-7.31 (3H, m), 6.52 (1H, dd, J=2.5,1.7 Hz), 5.78 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z437.1532 [(M+H)⁺; calculated for C₂₅H₁₈FN₆O: 437.1521].

Example 32-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,8-naphthyridin-3-one

Using the procedures described in Example 1, substituting ethyl4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate for ethyl4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Step 3), andsubstituting 2-iodotoluene for 2-fluoroiodobenzene (Step 6), the titledcompound was obtained: ¹H-NMR (400 MHz, CDCl₃) δ 8.70 (1H, dd, J=4.5,0.8 Hz), 8.67 (1H, d, J=8.2 Hz), 7.92 (1H, s), 7.72 (1H, s), 7.70 (2H,d, J=7.7 Hz), 7.52-7.45 (3H, m), 7.43-7.37 (1H, m), 7.35-7.28 (4H, m),6.48 (1H, m), 5.74 (2H, s), 2.30 (3H, s) ppm; high resolution massspectrometry (ES+) m/z 433.1794 [(M+H)⁺; calculated for C₂₆H₂₁N₆O:433.1771].

Example 42-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,7-naphthyridin-3-one

Step 1: Preparation of ethyl4-oxo-1-{[4-(1H-pyrazolo-1-yl)phenyl]methyl}-1,4-dihydro-1,7-naphthyridine-3-carboxylate:Using the procedures described in Example 1, substituting ethyl4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate for ethyl4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Step 3), the titledcompound was obtained.

Step 2: Preparation of ethyl4-oxo-1-{[4-(1H-pyrazolo-1-yl)phenyl]methyl}-1,4-dihydro-1,7-naphthyridine-3-carboxylate:Ethyl4-oxo-1-{[4-(1H-pyrazolo-1-yl)phenyl]methyl}-1,4-dihydro-1,7-naphthyridine-3-carboxylate(30 mg, 0.076 mmol) was dissolved in phosphorus oxychloride (0.22 mL,2.4 mmol, 30 equiv) and placed into a preheated oil bath at 40° C. for24 hours. The mixture was concentrated in vacuo and the residue wasconcentrated with toluene (3×5 mL). The resulting4-chloro-3-[(ethyloxy)carbony]-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,7-naphthyridin-1-iumsalt was dissovled in 1,2-dimethoxyethane (2 mL), treated with2-fluorophenylhydrazine (19 mg, 0.15 mmol, 2 equiv) and potassiumcarbonate (84 mg, 0.61 mmol, 8 equiv) and placed into a preheated oilbath at 80° C. for 1 hour. The mixture was cooled to ambienttemperature, poured into water (15 mL) and extracted withdichloromethane (2×15 mL). The combined organic extracts were dried withsodium sulfate, filtered and concentrated in vacuo. The residue waspurified by silica gel gradient chromatography (100:0 to 90:10;dichloromethane:methanol), providing the titled compound: ¹H-NMR (400MHz, d⁶-DMSO) δ 9.88 (1H, s), 8.95-8.90 (1H, m), 8.73 (1H, m), 8.73 (1H,m), 8.28 (1H, d, J=1.8 Hz), 8.05-8.02 (1H, m), 7.89 (2H, d, J=8.6 Hz),7.74 (1H, s), 7.69 (2H, d, J=8.7 Hz), 7.61-7.56 (1H, m), 7.53-7.48 (1H,m), 7.37-7.31 (2H, m), 6.55-6.54 (1H, m), 5.91 (2H, s) ppm; highresolution mass spectrometry (ES+) m/z 437.1531 [(M+H)⁺; calculated forC₂₅H₁₈FN₆O: 437.1521].

Example 52-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,6-naphthyridin-3-one

Using the procedures described in Example 4, substituting ethyl4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylate for ethyl4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Example 1, Step 3),the titled compound was obtained: ¹H-NMR (400 MHz, d⁶-DMSO) δ 9.54 (1H,s), 9.01 (1H, s), 8.67 (1H, s), 8.22 (1H, d, J=2.6 Hz), 7.80 (2H, d,J=8.8 Hz), 7.77 (1H, br s), 7.71 (1H, m), 7.65-7.61 (1H, m), 7.55-7.49(1H, m), 7.49 (2H, d, J=8.6 Hz), 7.38-7.33 (2H, m), 6.52-6.51 (1H, m),5.77 (2H, s) ppm; low resolution mass spectrometry (ES+) m/z 437.0[(M+H)⁺; calculated for C₂₅H₁₈FN₆O: 437.1].

Example 62-(2-Methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[3′,4′:4,5]-pyrido[2,3-b]pyrazin-3-one

Using the procedures described in Example 4, substituting ethyl8-oxo-5,8-dihydropyrido[2,3-b]pyrazine-7-carboxylate for ethyl4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Example 1, Step 3),and, substituting 2-methylphenylhydrazine for 2-fluorophenylhydrazine(Step 2), the titled compound was obtained: ¹H-NMR (400 MHz, CDCl₃) δ8.79 (1H, d, J=2.2 Hz), 8.65 (1H, d, J=2.2 Hz), 8.62 (1H, s), 7.92 (1H,d, J=2.5 Hz), 734-7.70 (3H, m), 7.49 (2H, d, J=8.7 Hz), 7.45-7.41 (1H,m), 7.33-7.24 (3H, m), 6.48 (1H, dd, J=2.4, 1.7 Hz), 5.67 (2H, s), 2.31(3H, s) ppm; low resolution mass spectrometry (ES+) m/z 433.9 [(M+H)⁺;calculated for C₂₅H₂₀N₇O: 434.2].

Example 75-(Biphenyl-4-ylmethyl)-2-(2-fluorophenyl)-5,6,7,8-tetrahydrocyclopenta[b]pyrazolo[3,4-d]pyridine-3(2H)-one

Step 1: Preparation of ethyl1-(biphenyl-4-ylmethyl)-4-thioxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate:Using the procedures described in Example 1, substituting ethyl4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate forethyl 4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Step 3), and,substituting 4-(bromomethyl)biphenyl for1-[4-(bromomethyl)phenyl]-1H-pyrazole (Step 3), the titled compound wasobtained.

Step 2: Preparation of5-(biphenyl-4-ylmethyl)-2-(2-fluorophenyl)-5,6,7,8-tetrahydrocyclopenta[b]pyrazolo[3,4-d]pyridine-3(2H)-one:Ethyl1-(biphenyl-4-ylmethyl)-4-thioxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate(0.30 g, 0.77 mmol) was suspended in ethanol (10 mL) and treated with2-fluorophenylhydrazine hydrochloride (0.38 g, 2.3 mmol, 3 equiv) andpotassium carbonate (0.64 g, 4.6 mmol, 6 equiv). The mixture was placedinto a preheated oil bath at 80° C. for 24 hours, cooled to ambienttemperature and concentrated in vacuo. The residue was treated withwater (20 mL) and extracted with ethyl acetate (2×50 mL). The combinedorganic extracts were dried with sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (100:0 to 90:10; chloroform:methanol), providing thetitled compound: ¹H-NMR (400 MHz, CDCl₃) δ 8.29 (1H, s), 7.61-7.56 (5H,m), 7.47-7.44 (2H, m), 7.40-7.30 (2H, m), 7.21-7.19 (2H, m), 5.20 (2H,s), 3.08 (2H, t, J=7.5 Hz), 2.94 (2H, t, J=7.5 Hz), 2.23 (2H, quin,J=7.5 Hz) ppm; low resolution mass spectrometry (ES+) m/z 436.1 [(M+H)⁺;calculated for C₂₈H₂₃FN₃O: 436.2].

Example 82-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-5,6,7,8-tetrahydrocyclopenta[b]pyrazolo[3,4-d]pyridine-3(2H)-one

Step 1: Preparation of ethyl4-oxo-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate:Using the procedures described in Example 1, substituting ethyl4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate forethyl 4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Step 3), thetitled compound was obtained.

Step 2: Preparation of2-(2-fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-5,6,7,8-tetrahydrocyclopenta[b]pyrazolo[3,4-d]pyridine-3(2H)-one:Using the procedures described in Example 4, substituting ethyl4-oxo-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylatefor ethyl4-oxo-1-{[4-(1H-pyrazolo-1-yl)phenyl]methyl}-1,4-dihydro-1,7-naphthyridine-3-carboxylate,the titled compound was obtained: ¹H-NMR (400 MHz, CDCl₃) δ 8.84 (1H,s), 7.94 (1H, s), 7.76 (2H, d, J=8.2 Hz), 7.60-7.56 (1H, m), 7.42-7.38(1H, m), 7.29-7.22 (4H, m), 6.50 (1H, m), 5.31 (2H, s), 3.12 (2H, t,J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz), 2.27 (2H, quin, J=7.5 Hz) ppm; lowresolution mass spectrometry (ES+) m/z 426.0 [(M+H)⁺; calculated forC₂₅H₂₁FN₅O: 426.2].

Example 92-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-d]pyridine-3(2H)-one

Using the procedures described in Example 8, substituting ethyl4-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate for ethyl4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (Step1), the titled compound was obtained: ¹H-NMR (400 MHz, d⁶-DMSO) δ 8.87(1H, s), 8.48 (1H, d, J=2.6 Hz), 7.86 (2H, d, J=8.4 Hz), 7.74 (1H, d,J=1.6 Hz), 7.55-7.51 (1H, m), 7.44-7.32 (3H, m), 7.28 (2H, d, J=8.7 Hz),6.55-6.54 (1H, m), 5.48 (2H, s), 2.62-2.60 (4H, m), 1.80-1.70 (2H, m),1.70-1.60 (2H, m) ppm; low resolution mass spectrometry (ES+) m/z 440.0[(M+H)⁺; calculated for C₂₆H₂₃FN₅O: 440.2].

Example 10(±)-2-(2-Fluorophenyl)-9-(prop-2-en-1-yloxy)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[4,3-c]quinolin-3-one

Step 1: Preparation of (±)-ethyl5-hydroxy-4-oxo-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate:Using the procedures described in Example 1, substituting (±)-ethyl5-hydroxy-4-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate for ethyl4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Step 3), the titledcompound was obtained.

Step 2: Preparation of (±)-ethyl4-oxo-5-(prop-2-en-1-yloxy)-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,4,4,5,6,7,8-hexahydroquinoline-3-carboxylate:(±)-Ethyl5-hydroxy-4-oxo-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate(0.26 g, 0.65 mmol) was dissolved in dichloromethane (7 mL) and treatedwith O-allyl-2,2,2-trichloroacetimidate (0.26 g, 1.3 mmol, 2 equiv) andtrifluoromethanesulfonic acid (0.058 mL, 0.65 mmol, 1 equiv). Afterstirring for 4 hours at ambient temperature, the mixture was dilutedwith chloroform (50 mL), washed with water (1×15 mL) and brine (1×15mL), dried with sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (100:0 to 90:10;chloroform:methanol), providing the titled compound.

Step 3: Preparation of(±)-2-(2-fluorophenyl)-9-(prop-2-en-1-yloxy)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[4,3-c]quinolin-3-one:Using the procedures described in Example 4, substituting (±)-ethyl4-oxo-5-(prop-2-en-1-yloxy)-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,4,5,6,7,8-hexahydroquinoline-3-carboxylatefor ethyl4-oxo-1-{[4-(1H-pyrazolo-1-yl)phenyl]methyl}-1,4-dihydro-1,7-naphthyridine-3-carboxylate(Step 2), the titled compound was obtained: ¹H-NMR (400 MHz, CDCl₃) δ8.28 (1H, s), 7.93 (1H, d, J=2.5 Hz), 7.75-7.51 (3H, m), 7.66-7.61 (1H,m), 7.34-7.29 (1H, m), 7.26-7.19 (2H, m), 7.18 (2H, d, J=8.4 Hz),6.50-6.49 (1H, m), 6.09-6.00 (1H, m), 5.32 (1H, dq, J=17.1, 1.3 Hz),5.20 (2H, s), 5.16 (1H, br d J=10.5 Hz), 4.85 (1H, m), 4.41-4.30 (2H,m), 2.72 (1H, dd, J=17.7, 5.7 Hz), 2.49-2.40 (1H, m), 2.18-2.06 (2H, m),1.88-1.80 (1H, m), 1.52 (1H, tt, J=14.2, 3.2 Hz) ppm; low resolutionmass spectrometry (ES+) m/z 495.9 [(M+H)⁺; calculated for C₂₉H₂₇FN₅O₂:496.2].

Example 11(±)-2-(2-Fluorophenyl)-9-hydroxy-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[4,3-c]quinolin-3-one

(±)-2-(2-Fluorophenyl)-9-(prop-2-en-1-yloxy)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[4,3-c]quinolin-3-one(Example 10, 26 mg, 0.052 mmol) was dissolved in dichloromethane (2 mL)and treated with tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016mmol, 0.3 equiv) and para-toluenesulfinic acid (11 mg, 0.068 mmol, 1.3equiv). After stirring for 30 minutes at ambient temperature, themixture was concentrated in vacuo and purified by silica gel gradientchromatography (100:0 to 90:10; chloroform:methanol), providing thetitled compound: ¹H-NMR (400 MHz, CDCl₃) δ 8.35 (1H, s), 7.93 (1H, d,J=2.5 Hz), 7.75-7.73 (3H, m), 7.63-7.59 (1H, m), 7.37-7.31 (1H, m),7.26-7.20 (2H, m), 7.16 (2H, d, J=8.6 Hz), 6.50-6.49 (1H, m), 5.23 (2H,s), 5.20-5.17 (1H, m), 4.38 (1H, br s), 2.66-2.52 (2H, m), 2.15-2.00(2H, m), 1.84-1.69 (2H, m) ppm; high resolution mass spectrometry (ES+)m/z 456.1844 [(M+H)⁺; calculated for C₂₆H₂₃FN₅O₂: 456.1830].

Example 122-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,-dihydro-3H-pyrazolo[4,3-d]thieno[3,2-b]pyridin-3-one

Using the procedures described in Example 4, substituting ethyl7-oxo-4,7-dihydrothieno[3,2-b]pyridine-3-carboxylate for ethyl4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Example 1, Step 3),the titled compound was obtained: ¹H-NMR (400 MHz, d⁶-DMSO) δ 9.10 (1H,s), 8.47 (1H, d, J=2.5 Hz), 8.00 (1H, d, J=5.6 Hz), 7.84 (2H, d, J=8.6Hz), 7.73 (1H, d, J=1.6 Hz), 7.61 (1H, d, J=5.6 Hz), 7.57 (1H, dd,J=7.6, 1.4 Hz), 7.51 (2H, d, J=8.6 Hz), 7.47-7.36 (2H, m), 7.32 (1H, td,J=7.7, 1.6 Hz), 6.53 (1H, d, J=2.4, 1.8 Hz), 5.73 (2H, s) ppm; highresolution mass spectrometry (ES+) m/z 442.1140 [(M+H)⁺; calculated forC₂₄H₁₇FN₅OS: 442.1133].

Example 132-(2-Methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,-dihydro-3H-pyrazolo[3,4-d]thieno[3,2-b]pyridin-3-one

Using the procedures described in Example 4, substituting ethyl7-oxo-4,7-dihydrothieno[3,2-b]pyridine-3-carboxylate for ethyl4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Example 1, Step 3),and substituting 2-methylphenylhydrazine for 2-fluorophenylhydrazine,the titled compound was obtained: ¹H-NMR (400 MHz, CDCl₃) δ 8.45 (1H,s), 7.92 (1H, d, J=2.6 Hz), 7.75-7.71 (3H, m), 7.56 (1H, d, J=5.6 Hz),7.46-7.41 (1H, m), 7.33-7.26 (5H, m), 7.17 (1H, d, J=5.6 Hz), 6.49-6.48(1H, m), 5.47 (2H, s), 2.33 (3H, s) ppm; high resolution massspectrometry (ES+) m/z 438.1404 [(M+H)⁺; calculated for C₂₅H₂₀N₅OS:438.1383].

Example 142-(2-Fluorophenyl)-5-[(1-methyl-1H-indazol-5-yl)methyl]-2,5,-dihydro-3H-pyrazolo[4,3-d]thieno[3,2-b]pyridin-3-one

Step 1: Preparation of (1-methyl-1H-indazol-5-yl)methylmethanesulfonate: indazol-5-yl)methanol (0.15 g, 0.92 mmol) wasdissolved in dichloromethane (3 mL), cooled to 0° C. and treated withtriethylamine (0.14 mL, 1.0 mmol, 1.1 equiv) and methanesulfonylchloride (0.079 mL, 1.0 mmol, 1.1 equiv). After stirring for 2 hours,the mixture was treated with additional triethylamine (0.14 mL, 1.0mmol, 1.1 equiv) and methanesulfonyl chloride (0.079 mL, 1.0 mmol, 1.1equiv). After an additional 1 hour, the mixture was diluted withdichloromethane (100 mL), washed with sodium bicarbonate (15 mL, aqueoussaturated) and brine (15 mL), dried with sodium sulfate, filtered andconcentrated in vacuo, providing the titled compound.

Step 2: Preparation of2-(2-fluorophenyl)-5-[(1-methyl-1H-indazol-5-yl)methyl]-2,5,-dihydro-3H-pyrazolo[4,3-d]thieno[3,2-b]pyridin-3-one:Using the procedures described in Example 4, substituting ethyl7-oxo-4,7-dihydrothieno[3,2-b]pyridine-3-carboxylate for ethyl4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Example 1, Step 3),and substituting (1-methyl-1H-indazol-5-yl)methyl methanesulfonate for1-[4-(bromomethyl)phenyl]-1H-pyrazole (Example 1, Step 3), the titledcompound was obtained: ¹H-NMR (400 MHz, CDCl₃) δ 8.37 (1H, s), 7.97 (1H,d, J=0.8 Hz), 7.65-7.61 (1H, m), 7.60 (1H, m), 7.56 (1H, d, J=5.6 Hz),7.43 (1H, d, 8.7 Hz), 7.37-7.31 (1H, m), 7.26-7.21 (4H, m), 5.54 (2H,s), 4.08 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z430.1125 [(M+H)⁺; calculated for C₂₃H₁₇FN₅OS: 430.1132].

Example 152-(3,5-Dichloropyridin-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,-dihydro-3H-pyrazolo[3,4-d]thieno[3,2-b]pyridin-3-one

Using the procedures described in Example 4, substituting ethyl7-oxo-4,7-dihydrothieno[3,2-b]pyridine-3-carboxylate for ethyl4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (Example 1, Step 3),and substituting 3,5-dichloro-4-hydrazinopyridine for2-fluorophenylhydrazine, the titled compound was obtained: ¹H-NMR (400MHz, d⁶-DMSO) δ 9.16 (1H, s), 8.87 (2H, s), 8.47 (1H, d, J=2.5 Hz), 8.05(1H, d, J=5.7 Hz), 7.85 (2H, d, J=8.7 Hz), 7.73 (1H, d, J=1.6 Hz), 7.65(1H, d, J=5.6 Hz), 7.55 (2H, d, J=8.8 Hz), 6.54 (1H, dd, J=2.4, 1.7 Hz),5.74 (2H, s) ppm; low resolution mass spectrometry (ES+) m/z 493.1[(M+H)⁺; calculated for C₂₃H₁₅Cl₂N₆OS: 493.0].

Example 165-{[4-(1H-Pyrazol-1-yl)phenyl]methyl}-2-pyridin-4-yl-2,5,-dihydro-3H-pyrazolo[3,4-d]thieno[3,2-b]pyridin-3-one

2-(3,5-Dichloropyridin-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,-dihydro-3H-pyrazolo[3,4-d]thieno[3,2-b]pyridin-3-one(Example 15, 15 mg, 0.030 mmol), ammonium formate (2.9 mg, 0,046 mmol,1.5 equiv) and 1,1′-bis(diphenylphosphino)ferroenedichloro palladium(II) dichloromethane complex (4.4 mg, 6.1 lima 0.2 equiv) were combinedin methanol (5 mL) and placed into a preheated oil bath at 70° C. for 14hours. The mixture was cooled to ambient temperature and concentrated invacuo. The residue was purified by silica gel gradient chromatography(100:0 to 85:15; chloroform:methanol), providing the titled compound:¹H-NMR (400 MHz, d⁶-DMSO) δ 9.28 (1H, s), 8.76 (2H, br d, J=5.5 Hz),8.57 (2H, br d, J=5.5 Hz), 8.48 (1H, d, J=2.5 Hz), 8.16 (1H, d, J=5.6Hz), 7.84 (2H, d, J=8.6 Hz), 7.73 (1H, d, J=1.5 Hz), 7.68 (1H, d, J=5.6Hz), 7.53 (2H, d, J=8.6 Hz), 6.53 (1H, dd, J=2.4, 1.8 Hz), 5.77 (2H, s)ppm; high resolution mass spectrometry (ES+) m/z 425.1184 [(M+H)⁺;calculated for C₂₃H₁₇N₆OS: 425.1179].

Biological Utility

The utility of the compounds as M1 receptor positive allostericmodulators may be demonstrated by methodology known in the art,including by the assay described below. The assay is designed to selectcompounds that possess modulator activity at the acetylcholinemuscarinic M1 receptor or other muscarinic receptors expressed inCHOnfat cells by measuring the intracellular calcium with a FLIPR³⁸⁴Fluorometric Imaging Plate Reader System. The assay studies the effectof one or several concentrations of test compounds on basal oracetylcholine-stimulated Ca²⁺ levels using FLIPR.

Compounds are prepared and subjected to a preincubation period of 4 min.Thereafter, a single EC₂₀ concentration of acetylcholine is added toeach well (3 nM final). The intracellular Ca²⁺ level of each sample ismeasured and compared to an acetylcholine control to determine anymodulatory activity.

Cells: CHOnfat/hM1, hM2, hM3 or hM4 cells are plated 24 hr before theassay at a density of 18,000 cells/well (100 up in a 384 well plate.CHOnfat/hM1 and CHOnfat/hM3 Growth Medium: 90% DMEM (Hi Glucose); 10% HIFBS; 2 mM L-glutamine; 0.1 mM NEAA; Pen-Strep; and 1 mg/ml Geneticin,are added. For M2Gqi5CHOnfat and M4Gqi5CHOnfat cells, an additional 600μg/ml hygrornycin is added.

Equipment: 384 well plate, 120 μL addition plate; 96-well Whatman 2 mlUniplate Incubator, 37° C., 5% CO₂; Skatron EMBLA-384 Plate Washer;Multimek Pipetting System; Genesis Freedom 200 System; Mosquito System;Temo Nanolitre Pipetting System; and FLIPR³⁸⁴ Fluorometric Imaging PlateReader System are used.

Buffers. Assay Buffer: Hanks Balanced Salt Solution, with 20 mM Hepes,2.5 mM Probenecid (Sigma P-8761) first dissolved in 1 N NaOH, 1% BovineSerum Albumin (Sigma A-9647). Dye Loading Buffer: Assay Buffer plus 1%Fetal Bovine Serum and Fluo-4AM/Pluronic Acid Mixture. 2 mM Fluo-4AMester stock in DMSO (Molecular Probes F-14202) Concentration of 2 μM inbuffer for a final concentration of 1 μM in Assay. 20% Pluronic AcidSolution stock, with concentration of 0.04% in Buffer, 0.02% in Assay.

65 μL of 2 mM Fluo-4AM are mixed with 130 μL of 20% Pluronic Acid. Theresulting solution and 650 μL FBS is added to the assay buffer for atotal volume of 65 mL. Positive Controls: 4-Br-A23187: 10 mM in DMSO;final concentration 10 μM. Acetylcholine: 10 mM in water, working stockat both 20 μM and 30 μM in assay buffer, final concentration of 10 μM.This is used to check the maximum stimulation of the CHOK1/hM1 cells. 20μM (2×) acetylcholine is added in the preincubation part of the assay,and the 30 μM (3×) stock is added in the second part.(EC₂₀)Acetylcholine: 10 mM in water, working stock of 9 nM (3×), andfinal concentration in assay is 3 nM. This is used after thepreincubation with test compounds. Addition of the EC₂₀ Acetylcholine toeach well with a test compound will ascertain any modulator activity. 24wells contain 3 nM Acetylcholine alone as a control.

Determining Activity of Putative Compounds:

Screening Plate Compounds are titrated in 96-well plates (columns 2-11),100% DMSO, started at a concentration of 15 mM (150× stockconcentration), and 3-fold serial dilutions using Genesis Freedom200System. Four 96-well plates are combined into a 384-well plate usingMosquito Nanolitre Pipetting System by transferring 1 μl of serialdiluted compounds to each well, and 1 mM acetylcholine (100× stockconcentration) were added as a control. Using Temo, 49 μl assay bufferis added to each well of the 384-well plate right before assay.

In a 96-well Whatman 2 ml Uniplate, 9 nM Acetylcholine (3×) is pipettedinto wells corresponding to the screening compounds, and into controlwells. The 30 μM acetylcholine control (3×) is added into control wells,and the 3× agonist plate is transferred into a 384 well plate.

Cells are washed three times with 100 μL of buffer, leaving 304 ofbuffer in each well. Using Multimek, 30 μL of Dye Loading Buffer isadded into each well and incubated at 37° C., 5% CO₂ for up to one hr.

After 60 min, the cells are washed three times with 100 μL of buffer,leaving 30 μL of buffer in each well. The cell plate, screening plate,and agonist addition plates are placed on the platform in the FLIPR andthe door closed. A signal test to check background fluorescence andbasal fluorescence signal is performed. Laser intensity is adjusted ifnecessary.

4 min of preincubation with the test compounds is provided to determineany agonist activity on the M1 receptor by comparison to the 1 mMacetylcholine control. After preincubation, the EC₂₀ value ofacetylcholine (3 nM final) is added to determine any modulator activity.

A further description of the muscarinic FLIPR assay can be found inInternational patent application WO2004/073639.

In particular, the compounds of the following examples had activity inthe aforementioned assay, generally with an IP (inflection point) of 10μM (10,000 nM) or less. The inflection point is calculated from theFLIPR values, and is a measure of activity. Such a result is indicativeof the intrinsic activity of the compounds in use as M1 allostericmodulators.

IP values from the aforementioned assay for representative exemplarycompounds of the invention (as described herein) are provided below inTable 1 below:

IP Value Example (nM) 1 160 2 318 4 7668 6 759 8 770 9 360 11 1296 12 2013 108 15 65

The following abbreviations are used throughout the text:

-   Me: methyl-   Et: ethyl-   Bu: butyl-   t-Bu: tert-butyl-   Ar: aryl-   Ph: phenyl-   Bn: benzyl-   Ac: acetyl-   DMF: dimethylformamide-   DME: 1,2-dimethoxyethane-   DMSO: dimethylsulfoxide-   DMEM: Dulbecco's Modified Eagle Medium (High Glucose)-   FBS: fetal bovine serum-   rt: room temperature-   aq: aqueous-   HPLC: high performance liquid chromatography-   MS: mass spectrometry

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims that follow and that such claims be interpreted as broadly asis reasonable.

1-17. (canceled)
 18. A compound of formula (I):

wherein ring A is saturated or unsaturated, and is formed from 3 or 4ring atoms, selected from the group consisting of S, O, CH, CH₂, N andNH, wherein one or more of the ring atoms is optionally substituted byone or more R¹; R¹ is optionally present at one or more of the ring Aatoms, and each R¹ is selected from the group consisting of (1) halogen,(2) —C₁₋₆ alkyl, or (3) —OC₁₋₆ alkyl, (4) hydroxyl, wherein the alkyl R¹moiety is optionally substituted with one or more (a) halogen, (b)hydroxy, (c) —O—C₁₋₆ alkyl, (d) —C₂₋₈ alkenyl, R² is optionally presentat one or more of the ring carbon atoms, and each R² is selected fromthe group consisting of (1) halogen, (2) —C₁₋₆ alkyl, or (3) —OC₁₋₆alkyl, (4) hydroxyl, R³ is selected from the group consisting of (1)hydrogen, (2) —C₁₋₆ alkyl, (3) —C₆₋₁₀ aryl, (4) heteroaryl, which is anaromatic cyclic group, having from five to twelve ring atoms, the ringatoms selected from C, O, N, N→O or S, at least one of which is O, N,N→O or S, wherein the alkyl, aryl or heteroaryl moiety is optionallysubstituted with one or more (a) halogen, (b) hydroxyl, (c) —C₁₋₆ alkyl,(d) —O—C₁₋₆ alkyl, (e) —C₃₋₈ cycloalkyl, or (f) —C₆₋₁₀ aryl, or R² andR³ together form a chain of 3 or 4 ring atoms, selected from the groupconsisting of S, CH, CH₂, N and NH, wherein one or more of the ringatoms is optionally substituted by one or more (a) halogen, (b) —C₁₋₆alkyl, or (c) —OC₁₋₆ alkyl; R⁴ is optionally present at one or more ofthe ring carbon atoms, and each R⁴ is selected from the group consistingof (1) halogen, (2) —C₁₋₆ alkyl, (3) —OC₁₋₆ alkyl, or (4) hydroxyl; andX is N or CH; or a pharmaceutically acceptable salt thereof.
 19. Acompound of claim 18, wherein A forms one of the following rings


20. A compound of claim 18 wherein R² is optionally present at one ofthe ring carbon atoms, and R² is selected from the group consisting of(1) halogen, (2) —C₁₋₆ alkyl, or (3) —OC₁₋₆ alkyl.
 21. A compound of anyof claims 18 wherein R³ is selected from the group consisting of (1)—C₆₋₁₀ aryl, or (2) heteroaryl, which is an aromatic cyclic group,having from five to twelve ring atoms, the ring atoms selected from C,O, N, N→O or S, at least one of which is O, N, N→O or S, wherein thealkyl, aryl or heteroaryl moiety is optionally substituted with one ormore (a) halogen, (b) hydroxyl, or (c) —C₁₋₆ alkyl.
 22. A compound ofclaim 21, wherein R³ is imidazolyl or phenyl.
 23. A compound of claim 18wherein R⁴ is present at one of the ring carbon atoms, and is selectedfrom the group consisting of (1) halogen, or (2) —C₁₋₆ alkyl.
 24. Acompound of claim 18 wherein X is C.
 25. A compound of claim 18, whereinthe compound of formula (I) is a compound of formula (II)

and pharmaceutically acceptable salts thereof, wherein A, R¹, R² and R⁴are defined in claim
 18. 26. A compound of claim 25, wherein A forms oneof the following rings


27. A compound of claim 25, wherein R² is optionally present at one ofthe ring carbon atoms, and R² is selected from the group consisting of(1) halogen, (2) —C₁₋₆ alkyl, or (3) —OC₁₋₆ alkyl.
 28. A compound ofclaim 25, wherein R⁴ is present at one of the ring carbon atoms, and isselected from the group consisting of (1) halogen, or (2) —C₁₋₆ alkyl.29. A compound of claim 18, which is selected from the group consistingof:2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,5-naphthyridin-3-one;2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,8-naphthyridin-3-one;2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,8-naphthyridin-3-one;2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,7-naphthyridin-3-one;2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,6-naphthyridin-3-one;2-(2-Methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[3′,′:4,5]-pyrido[2,3-b]pyrazin-3-one;5-(Biphenyl-4-ylmethyl)-2-(2-fluorophenyl)-5,6,7,8-tetrahydrocyclopenta[b]pyrazolo[3,4-d]pyridine-3(2H)-one;2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-5,6,7,8-tetrahydrocyclopenta[b]pyrazolo[3,4-d]pyridine-3(2H)-one;2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-d]pyridine-3(2H)-one;(±)-2-(2-Fluorophenyl)-9-(prop-2-en-1-yloxy)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[4,3-c]quinolin-3-one;(±)-2-(2-Fluorophenyl)-9-hydroxy-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[4,3-c]quinolin-3-one;2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,-dihydro-3H-pyrazolo[4,3-d]thieno[3,2-b]pyridin-3-one;2-(2-Methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,-dihydro-3H-pyrazolo[3,4-d]thieno[3,2-b]pyridin-3-one;2-(2-Fluorophenyl)-5-[(1-methyl-1H-indazol-5-yl)methyl]-2,5,-dihydro-3H-pyrazolo[4,3-d]thieno[3,2-b]pyridin-3-one;2-(3,5-Dichloropyridin-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,-dihydro-3H-pyrazolo[3,4-d]thieno[3,2-b]pyridin-3-one;5-{[4-(1H-Pyrazol-1-yl)phenyl]methyl}-2-pyridin-4-yl-2,5,-dihydro-3H-pyrazolo[3,4-c]thieno[3,2-b]pyridin-3-one;or a pharmaceutically acceptable salt thereof.
 30. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 18 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 31. A pharmaceutical compositionfor the treatment of a disease or disorder mediated by the muscarinic M1receptor, wherein the disease or disorder is selected from the groupconsisting of Alzheimer's disease, schizophrenia, pain or sleepdisorders, comprising a therapeutically effective amount of a compoundof claim 18 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 32. Use of a pharmaceuticalcomposition of claim 31 for the treatment of a disease or disordermediated by the muscarinic M1 receptor, wherein the disease or disorderis selected from the group consisting of Alzheimer's disease,schizophrenia, pain or sleep disorders.
 33. Use of a compound of claim18 or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, for the manufacture of a medicament for thetreatment of a disease or disorder mediated by the muscarinic M1receptor, wherein the disease or disorder is selected from the groupconsisting of Alzheimer's disease, schizophrenia, pain or sleepdisorders.
 34. A method of treating a disease or disorder mediated bythe muscarinic M1 receptor, wherein the disease or disorder is selectedfrom the group consisting of Alzheimer's disease, schizophrenia, pain orsleep disorders in a patient in need thereof, comprising administeringto the patient a therapeutically effective amount of a compound of claim1 or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.